My laboratory studies the structure-function relationships of the B-ZIP class of sequence-specific DNA binding dimeric proteins. Over 50 B-ZIP genes have been identified in the mammalian genome. In the most general terms, B-ZIP proteins both activate and repress gene expression in response to physiological changes, be it growth factors (FOS), stress (ATF2), neuronal signaling (CREB), or metabolic changes (CEBP). We want to study B-ZIP transcriptional function using dominant-negatives (DN's) that inhibit B-ZIP DNA binding. A problem with the design of such reagents is that B-ZIP proteins become stabilized by binding DNA. We have overcome this problem by extending the dimerization domain into the basic region to produce A-ZIP's. The A represents an N-terminal Acidic amphipathic extension of the leucine zipper that replaces the basic region critical for sequence-specific DNA binding of the B-ZIP dimer. These A-ZIP proteins act as D-N's by inhibiting the DNA binding of B-ZIP proteins because of the stabilization that occurs through the interaction of the acidic extension with the basic region of the B-ZIP domain. They form an alpha-helical coiled coil extension of the leucine zipper. The pathology of excited stress pathways caused by B-ZIP proteins can be examined using these A-ZIPs. Ultimately, we hope to use these gene-based A-ZIPs as adjuvants with other medical approaches to cure human disease, particularly chemotherapy resistant cancers. The hypothesis driving this work is that direct transcriptional targets of a B-ZIP protein can be identified by expression of the corresponding A- ZIP protein.